Bile acids are synthesized in the liver from cholesterol and are essential to normal digestive and liver functions. The biological and chemical properties of bile acids have led to their use as therapeutic agents in the treatment of liver disease, cancer and for dissolving gallstones (Conference Proceedings Bile Acids 1993 and the Future California, USA, March 11-14,1993). For example, ursodeoxycholic acid has been shown to be an effective therapeutic agent in the treatment of primary biliary cirrhosis.
In biological systems, the amphiphilicity of bile salts assists in dissolving lipid-soluble substrates by facilitating contact with hydrolytic enzymes. For example, in the presence of bile salts, carboxylic ester hydrolase (cholesterol esterase) is known to hydrolyze water-insoluble esters, such as cholesterol, vitamin A, vitamin D.sub.3 and vitamin E.
Recently, bile acids have been studied for their potential to deliver a drug molecule specifically into the liver and the biliary system (Kramer, W. et al, J Bio Chem 267: 26: 18598-18604; 1992). The studies suggest that hybrid molecules formed by covalent linkage of a drug to a bile salt are promising options for the delivery of liver-specific drugs and for enhanced intestinal absorption of drugs that are otherwise poorly absorbed.
Bile acids could also potentially play an important role in the treatment of cancer patients. One of the problems encountered during chemotherapy is that the efficacy of chemotherapeutic drugs is reduced because the drugs are rapidly metabolized in vivo by enzymes responsible for removing xenobiotics from cells in a living system. Bile acids, however, are known to interact with these enzymes. For example, glucuronosyl transferase is inhibited by lithocholic acid, thereby preventing the removal of xenobiotics from cells. However, lithocholic acid is highly toxic and, therefore, unsuitable for use in the treatment of cancer patients. It will be appreciated by those skilled in the art that a derivative of lithocholic acid with a similar ability for inhibiting the rate of metabolism of xenobiotics, for example chemotherapeutic drugs, while demonstrating a reduced toxicity could be very useful.
In another important development, the structure of bile salts was found to affect the stereoselectivity of cholesterol esterase in the hydrolysis of stereoisomers of vitamin E acetate, namely (2R,4'R,8'R)- and (2S,4'R,8'R)-.alpha.-tocopheryl acetates (RRR-and SRR-.alpha.-TAc, respectively) (Zahalka, H. A. et al J Am Chem Soc 113: 7: 2797-2799; 1991). In the presence of cholic acid as the obligatory bile salt, the rate of hydrolysis of SRR-.alpha.-TAc was greater than that of the RRR-stereoisomer. However, when the obligatory bile salt was changed to glycocholate and to taurocholate, the rate of hydrolysis of the RRR-.alpha.-TAc was higher under similar reaction conditions, thereby indicating modulation of chiral recognition by changing the bile salt. These studies strongly suggest that chiral bile salts act, in this case, as a stereomodulator of enzymatic hydrolysis, rather than acting to solubilize the substrate. Modulation of chiral recognition is especially noteworthy in this example because the chiral center is separated by six bonds from the hydrolysis site.
One of the major problems in understanding the mechanisms of actions of bile acids is the lack of availability of a wide variety of bile acids with systematic modifications in their structures. It is believed that new bile acids with systematic modifications in their structures can play an important role in understanding their mechanistic actions in biological and chemical applications.
It is an object of the present invention to synthesize novel bile acids that are derived from cholic, deoxycholic, ursodeoxycholic and lithocholic acids. It is another object of the present invention to provide novel bile acids with systematic modifications in their structures for use in studying the mechanistic actions of the novel bile acids; in biological and chemical applications, including interaction with enzymes, effectiveness in the treatment of cancer and other diseases and as an agent for dissolving gallstones.